Author
Sarah E. O'Connor
Other affiliations: Massachusetts Institute of Technology, University of Cambridge, Norwich Research Park ...read more
Bio: Sarah E. O'Connor is an academic researcher from Max Planck Society. The author has contributed to research in topics: Catharanthus roseus & Medicine. The author has an hindex of 46, co-authored 139 publications receiving 6522 citations. Previous affiliations of Sarah E. O'Connor include Massachusetts Institute of Technology & University of Cambridge.
Topics: Catharanthus roseus, Medicine, Iridoid, Strictosidine, Secologanin
Papers published on a yearly basis
Papers
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TL;DR: The biosynthetic pathways for several representative terpene indole alkaloids are described in detail, showing a diverse array of structures and biological activities.
761 citations
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TL;DR: Advances in both glycoconjugate chemical synthesis and glycoprotein expression methods have increased the availability of these once elusive biopolymers, and the application of spectroscopic methods has begun to illuminate the various ways in which the saccharide affects the structure, function and stability of the proteins.
384 citations
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TL;DR: It is demonstrated how strictosidine can be produced de novo in a Saccharomyces cerevisiae host from 14 known monoterpene indole alkaloid pathway genes, along with an additional seven genes and three gene deletions that enhance secondary metabolism.
Abstract: The monoterpene indole alkaloids are a large group of plant-derived specialized metabolites, many of which have valuable pharmaceutical or biological activity. There are ∼3,000 monoterpene indole alkaloids produced by thousands of plant species in numerous families. The diverse chemical structures found in this metabolite class originate from strictosidine, which is the last common biosynthetic intermediate for all monoterpene indole alkaloid enzymatic pathways. Reconstitution of biosynthetic pathways in a heterologous host is a promising strategy for rapid and inexpensive production of complex molecules that are found in plants. Here, we demonstrate how strictosidine can be produced de novo in a Saccharomyces cerevisiae host from 14 known monoterpene indole alkaloid pathway genes, along with an additional seven genes and three gene deletions that enhance secondary metabolism. This system provides an important resource for developing the production of more complex plant-derived alkaloids, engineering of nonnatural derivatives, identification of bottlenecks in monoterpene indole alkaloid biosynthesis, and discovery of new pathway genes in a convenient yeast host.
361 citations
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TL;DR: The discovery of iridoid synthase is reported, a plant-derived enzyme that generates the iridoids ring scaffold, as evidenced by biochemical assays, gene silencing, co-expression analysis and localization studies, and the prospects of using unrelated reductases to generate artificial cyclic scaffolds are highlighted.
Abstract: Iridoids are a large family of bicyclic natural products that possess anticancer, anti-inflammatory, antifungal and antibacterial activities; here the essential cyclization step in their biosynthesis is identified, opening up the possibility of production of naturally occurring and synthetic variants of iridoids for use in pharmacy or agriculture.
291 citations
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Norwich Research Park1, University of Cambridge2, Polytechnic University of Valencia3, Leibniz Institute for Neurobiology4, Technische Universität Darmstadt5, Lawrence Berkeley National Laboratory6, Joint BioEnergy Institute7, Donald Danforth Plant Science Center8, University of Sheffield9, VTT Technical Research Centre of Finland10, Royal Holloway, University of London11, Weizmann Institute of Science12, University of Essex13, United States Department of Agriculture14, University of Wisconsin-Madison15, University of Copenhagen16, University of Oxford17, Aarhus University18, Wageningen University and Research Centre19, Cardiff University20, University of Warwick21, University of Bristol22
TL;DR: A standard for Type IIS restriction endonuclease-mediated assembly is described, defining a common syntax of 12 fusion sites to enable the facile assembly of eukaryotic transcriptional units.
Abstract: Inventors in the field of mechanical and electronic engineering can access multitudes of components and, thanks to standardization, parts from different manufacturers can be used in combination with each other. The introduction of BioBrick standards for the assembly of characterized DNA sequences was a landmark in microbial engineering, shaping the field of synthetic biology. Here, we describe a standard for Type IIS restriction endonuclease-mediated assembly, defining a common syntax of 12 fusion sites to enable the facile assembly of eukaryotic transcriptional units. This standard has been developed and agreed by representatives and leaders of the international plant science and synthetic biology communities, including inventors, developers and adopters of Type IIS cloning methods. Our vision is of an extensive catalogue of standardized, characterized DNA parts that will accelerate plant bioengineering.
235 citations
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TL;DR: The basis for the unique properties and rate enhancement for triazole formation under Cu(1) catalysis should be found in the high ∆G of the reaction in combination with the low character of polarity of the dipole of the noncatalyzed thermal reaction, which leads to a considerable activation barrier.
Abstract: The Huisgen 1,3-dipolar cycloaddition reaction of organic azides and alkynes has gained considerable attention in recent years due to the introduction in 2001 of Cu(1) catalysis by Tornoe and Meldal, leading to a major improvement in both rate and regioselectivity of the reaction, as realized independently by the Meldal and the Sharpless laboratories. The great success of the Cu(1) catalyzed reaction is rooted in the fact that it is a virtually quantitative, very robust, insensitive, general, and orthogonal ligation reaction, suitable for even biomolecular ligation and in vivo tagging or as a polymerization reaction for synthesis of long linear polymers. The triazole formed is essentially chemically inert to reactive conditions, e.g. oxidation, reduction, and hydrolysis, and has an intermediate polarity with a dipolar moment of ∼5 D. The basis for the unique properties and rate enhancement for triazole formation under Cu(1) catalysis should be found in the high ∆G of the reaction in combination with the low character of polarity of the dipole of the noncatalyzed thermal reaction, which leads to a considerable activation barrier. In order to understand the reaction in detail, it therefore seems important to spend a moment to consider the structural and mechanistic aspects of the catalysis. The reaction is quite insensitive to reaction conditions as long as Cu(1) is present and may be performed in an aqueous or organic environment both in solution and on solid support.
3,855 citations
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TL;DR: The division of synthesis and processing between the ER and the Golgi complex represents an evolutionary adaptation that allows efficient exploitation of the potential of oligosaccharides.
Abstract: N-linked oligosaccharides arise when blocks of 14 sugars are added cotranslationally to newly synthesized polypeptides in the endoplasmic reticulum (ER). These glycans are then subjected to extensive modification as the glycoproteins mature and move through the ER via the Golgi complex to their final destinations inside and outside the cell. In the ER and in the early secretory pathway, where the repertoire of oligosaccharide structures is still rather small, the glycans play a pivotal role in protein folding, oligomerization, quality control, sorting, and transport. They are used as universal “tags” that allow specific lectins and modifying enzymes to establish order among the diversity of maturing glycoproteins. In the Golgi complex, the glycans acquire more complex structures and a new set of functions. The division of synthesis and processing between the ER and the Golgi complex represents an evolutionary adaptation that allows efficient exploitation of the potential of oligosaccharides.
2,299 citations
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TL;DR: This review traces natural products drug discovery, outlining important drugs from natural sources that revolutionized treatment of serious diseases and effective drug development depends on multidisciplinary collaborations.
2,272 citations
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TL;DR: From a process involved in cell wall synthesis in archaea and some bacteria, N-linked glycosylation has evolved into the most common covalent protein modification in eukaryotic cells.
Abstract: From a process involved in cell wall synthesis in archaea and some bacteria, N-linked glycosylation has evolved into the most common covalent protein modification in eukaryotic cells. The sugars are added to nascent proteins as a core oligosaccharide unit, which is then extensively modified by removal and addition of sugar residues in the endoplasmic reticulum (ER) and the Golgi complex. It has become evident that the modifications that take place in the ER reflect a spectrum of functions related to glycoprotein folding, quality control, sorting, degradation, and secretion. The glycans not only promote folding directly by stabilizing polypeptide structures but also indirectly by serving as recognition "tags" that allow glycoproteins to interact with a variety of lectins, glycosidases, and glycosyltranferases. Some of these (such as glucosidases I and II, calnexin, and calreticulin) have a central role in folding and retention, while others (such as alpha-mannosidases and EDEM) target unsalvageable glycoproteins for ER-associated degradation. Each residue in the core oligosaccharide and each step in the modification program have significance for the fate of newly synthesized glycoproteins.
1,945 citations
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TL;DR: While the intrinsic complexity of natural product-based drug discovery necessitates highly integrated interdisciplinary approaches, the reviewed scientific developments, recent technological advances, and research trends clearly indicate that natural products will be among the most important sources of new drugs in the future.
1,760 citations